Etoricoxib–Betamethasone Combination Attenuates Inflammatory Nociception and Edema in Adjuvant-Induced Arthritis via Cytokine and Macrophage Axis Modulation

Background/Objectives: Acute inflammatory episodes demand rapid symptom control while limiting systemic exposure. We assessed whether co-therapy with the selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib and the corticosteroid betamethasone provides antinociceptive and anti-edema activity in a rat model with complete Freund’s adjuvant-induced arthritis (AIA). Methods: Male Wistar rats (n = 10/group) were allocated to seven groups: Intact, AIA disease control, indomethacin 5 mg/kg, etoricoxib 8 mg/kg, betamethasone 0.022 mg/kg, low-dose combination (4 + 0.011 mg/kg), and full-dose combination (8 + 0.022 mg/kg), administered orally once daily from Days 4 to 28. Paw edema, von Frey withdrawal thresholds, and clinical arthritis score were assessed longitudinally as area under the curve (AUC) values. Terminal joint tissues were profiled for cytokines, prostaglandin pathway mediators, and immune cell markers. Results: Both combinations reduced edema and improved mechanical thresholds. The full-dose combination exceeded either monotherapy regarding mechanical sensitivity and the arthritis index, consistent with additive activity. The low-dose combination matched full-dose monotherapies, consistent with a dose-reduction effect. Biomarker shifts indicated attenuated prostaglandin signaling and a pro-resolving cytokine balance. Conclusions: These findings support the further evaluation of etoricoxib–betamethasone co-therapy for acute inflammatory conditions.